Akhmetzyanova Ilseyar, Zelinskyy Gennadiy, Littwitz-Salomon Elisabeth, Malyshkina Anna, Dietze Kirsten K, Streeck Hendrik, Brandau Sven, Dittmer Ulf
Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, 45147 Essen, Germany;
Institute for Medical Biology of the University Hospital in Essen, University of Duisburg-Essen, 45122 Essen, Germany; and.
J Immunol. 2016 Jan 1;196(1):484-92. doi: 10.4049/jimmunol.1403039. Epub 2015 Nov 25.
Recent successes in immune therapeutic strategies aimed to improve control over tumor growth have sparked hope that long-lived control of cancer through stimulation of the immune system can be possible. However, the underlying immunological mechanisms that are induced by immunotherapeutic strategies are not well understood. In this study, we used the highly immunogenic Friend virus-induced FBL-3 tumor as a model to study the mechanisms of immunological tumor control by CD4(+) T cells in the course of CD137 (4-1BB) agonist immunotherapy in the absence of a CD8 T cell response. We demonstrate that treatment with a CD137 agonist resulted in complete FBL-3 tumor regression in CD8(+) T cell-deficient mice. CD137 signaling enhanced the production of proinflammatory cytokines and cytotoxic molecules in tumor-specific CD4(+) T cells. Interestingly, a subset of CD4(+)Foxp3(+) regulatory T cells was reprogrammed to eliminate immunogenic virus-induced tumor cells in response to CD137 agonist treatment. These cells expressed markers characteristic for Th cells (CD154) and produced the cytokine TNF-α or the T-box transcriptional factor Eomesodermin and granzyme B without loss of Foxp3 expression. Foxp3 Eomes double-positive CD4(+) T cells were capable of eliminating immunogenic virus-induced tumor cells in vivo. Thus, our data show that tumor-induced Foxp3(+)CD4(+) T cells can be reprogrammed into cytotoxic effector cells upon therapeutic costimulatory signaling and restore antitumor immunity.
旨在加强对肿瘤生长控制的免疫治疗策略最近取得的成功，引发了人们的希望，即通过刺激免疫系统对癌症进行长期控制是有可能的。然而，免疫治疗策略所诱导的潜在免疫机制尚未得到充分了解。在本研究中，我们使用高度免疫原性的Friend病毒诱导的FBL-3肿瘤作为模型，以研究在缺乏CD8 T细胞应答的情况下，CD137（4-1BB）激动剂免疫治疗过程中CD4(+) T细胞控制肿瘤免疫的机制。我们证明，用CD137激动剂治疗可导致CD8(+) T细胞缺陷小鼠的FBL-3肿瘤完全消退。CD137信号增强了肿瘤特异性CD4(+) T细胞中促炎细胞因子和细胞毒性分子的产生。有趣的是，一部分CD4(+)Foxp3(+)调节性T细胞被重新编程，以响应CD137激动剂治疗而消除免疫原性病毒诱导的肿瘤细胞。这些细胞表达Th细胞特征性标志物（CD154），并产生细胞因子TNF-α或T-box转录因子Eomesodermin和颗粒酶B，而不丧失Foxp3表达。Foxp3 Eomes双阳性CD4(+) T细胞能够在体内消除免疫原性病毒诱导的肿瘤细胞。因此，我们的数据表明，肿瘤诱导的Foxp3(+)CD4(+) T细胞在治疗性共刺激信号作用下可被重新编程为细胞毒性效应细胞，并恢复抗肿瘤免疫力。
